Summary

Methods

Overall study design: Study conducted in two identical parts,
results then combined. Part I: patients randomized to tPA vs. placebo,
assessed for effect of tPA 24 hours after stroke (and then 3 months later).
Assuming no major deleterious effect of tPA in Part I (at 24 hours), more
patients were then to be enrolled in part II: same randomization, also
assessed at 24 hours and 3 months. Both parts were stratified into two
equal groups by time from onset of symptoms to treatment: 0-90 mins and
90-180 mins. Although both parts were conducted identically, the primary
outcome in part I was the percentage of patients with significant improvement
at 24 hours, in part II it was the percentage of patients without significant
disability at 3 months.

Eligibility: main criteria: ischemic stroke with clearly defined
time of onset, CT scan without hemorrhage. Main exclusions related to risk
of hemorrhage (recent surgery, abnormal coags) and BP > 185/110.

Measurements: At baseline and 24 hours: NIH stroke scale
(NIHSS), a measurement of neurologic deficit on a 0-42 point scale. At
three months: three measurements of function: Barthel Index (ability
to perform ADL's), modified Rankin scale (overall function) and Glasgow
outcome scale (outcome, including death); the NIHSS; and a global test
statistic derived from these four measurements.

Repeat CT scans performed at 24 hours and 7-10 days, as well as whenever
any symptoms suggested hemorrhage. Major systemic bleeding and deaths recorded.

Results

In part I, 291 patients randomized, equally divided into tPA vs placebo
as well as 0-90 mins vs 91-180 mins. In part II, 333 patients randomized,
also equally distributed.

Percentage of patients with improvement at 24 hours (defined as
4-point improvement in NIHSS at 24 hours or complete resolution). This
was the primary outcome measured in part I. There was no statistically
significant difference noted in part I between tPA and placebo. Looking
at these same measurements for part II and for parts I-II combined, however,
there was a higher proportion of improvement for tPA in the 0-90 mins group
(59% vs 39 % in part II, p=0.02).

Percentage of patients with favorable outcome at 3 months (95 or
100 on Barthel; <=1 on Rankin; 1 on Glasgow; <= 1 on NIHSS): significantly
higher for tPA group than placebo. In part II, the global statistic derived
from these four measurements yielded an odds-ratio of favorable outcome
for tPA of 1.7 (p=0.008). The percentage of patients with favorable outcomes
from these four measurements in part II was Barthel: 50% for tPA vs 38%
for placebo; Rankin: 39% vs 26%; Glasgow: 44% vs 32%; NIHSS: 31% vs 20%.
Results were similar when parts I and II were combined, and for the two
time groups.

Mortality: no significant difference (17% tPA; 21% placebo)

Intracerebral hemorrhage: Within the first 36 hours of treatment,
among the tPA treated patients there were 16 symptomatic intracerebral
hemorrhages; none in the placebo group (p<0.001). Between 36 hours and
3 months, there 4 symptomatic intracerebral hemorrhages in the tPA group
and 2 in the placebo group. Of the 20 tPA group hemorrhages, 9 were fatal;
of the two placebo group hemorrhages, one was fatal. Asymptomatic intracerebral
bleeding was similar for tPA and placebo. Patients with symptomatic intracranial
hemorrhage had more severe deficits at baseline (median NIHSS at baseline
20, vs 14 for the entire study population).

Authors' Discussion

tPA yielded significant benefits at 3 months compared with placebo.
Other recent, large trials of thrombolytic therapy in stroke yielded no
benefit; according to the authors this is because these trials treated
many patients more than 3 hours after symptom onset, and/or because of
higher doses of thrombolytics and poorer BP control.

Editorial

G. del Zoppo from the Scripps Institute points out, in an editorial,
that although the European Cooperative Acute Stroke Study, another randomized
tPA study, found no benefit for tPA, when the results were re-analyzed
excluding 109 patients with protocol violations, a similar improvement
in the Rankin score was obtained. Dr. del Zoppo also points out that very
early intervention may decrease the incidence of treatment-related hemorrhage.
He also notes that studies looking only at short-term improvement or mortality
may miss a later improvement in functional results, as found in this study.

Comment

The two most problematic issues that this study raises, for me, are the
necessity to treat within 3 hours of symptom onset including a CT scan
and the fact that patients with worse deficits at baseline had a higher
tendency to hemorrhage.

Obtaining a quality CT scan, read by a qualified radiologist, so soon
after the onset of symptoms is very difficult. It might require triaging
probable stroke patients towards institutions that are set up to handle
this sort of protocol. A significant number of patients don't receive thrombolytic
therapy for acute MI because of delays in diagnosis; MI patients have a
window of opportunity felt to be around 6 hours, as a rule, and don't usually
require a procedure prior to treatment, making their treatment much easier
than that of CVA patients who, apparently, need to be caught within 3 hours
and clearly need a scan before therapy.

In this study, patients who had treatment-related intracerebral bleeding
had worse baseline neurological deficits. If it turns out that this sub-group
of patients does worse with thrombolysis, then this therapy might have
to be withheld from the group with the worst outcomes. This would not negate
the benefit of thrombolysis for those with lesser deficits, but might mean
that even very early intervention would not greatly impact on the disastrous
strokes that are so feared.

Reader comments

TPA is not available in Pakistan and would be too expensive in any case.
Can streptokinase or any other thrombolytic be used?

The major trials of streptokinase in stroke have not shown benefit
to date. The MAST trials (MAST-I was summarized here)
were halted prematurely because of excess mortality in the treatment group.
In these trials, streptokinase was administered within 6 hours of the onset
of symptoms; in the tPA trial (above), the lytic agent was administered
within three hours. Thus, the question arises -- what would the result
be if streptokinase were administered within a similar time frame?

One study from Australia tested streptokinase administered within
4 hours against placebo. It was also halted prematurely because of excess
mortality in the treatment group. In a subgroup analysis from this trial,
patients who were treated within three hours had a trend towards better
outcomes, but this did not achieve statistical significance (Donnan et
al. Streptokinase for Acute Ischemic Stroke With Relationship to Time of
Administration. JAMA.
1996;276:961-966). Thus, at present, it does not appear that streptokinase
is an acceptable alternative to tPA administered within three hours of
ischemic stroke. --mj

Date: Sun, 02 Mar
From: Mario Cicone <mciccone@nt.net>

In the same issue of NEJM, (Dec 14, 1995, pp 1588-1593), a study by
Richard Kay et. al. (abstract)
looked at the use of Low Molecular Weight Heparin (LMWH) for the treatment
of ischemic stroke. It seems to me that this study was favourable towards
its use in the first 48 hours post symptoms. There has been very little
criticism in subsequent letters to the Editor regarding this study.

I don't get it. Why has all the focus been on the NINDS t-PA study and
not on this one? Should we not be looking to use LMWH in acute ischemic
stroke??

MVC
M.D.

This is an interesting point. To summarize the Kay study on low
molecular weight heparin very briefly, 312 patients were randomized to
one of three groups: high dose LMWH, low dose LMWH and placebo, for 10
days post CVA. Among 245 patients who underwent a repeat CT scan at the
end of the treatment period, there was no evidence for increased intracranial
bleeding in the LMWH groups. The primary study outcome was all-cause death
or disability (dependency vis-a-vis activities of daily living). At three
months there was a non-significant trend favoring LMWH (poor outcomes:
53%, 60%, 64%). At six months the difference was significant (45%,
52%, 65%).

The NINDS study cannot be compared directly. However, if we use the
Barthel index of 95 or 100 to indicate a favorable outcome, then the percentage
of patients with unfavorable outcomes at three months were 48% in
the tPA group, vs. 62% in the placebo group. This was statistically significant.
As noted in the summary above, there was a greater incidence of symptomatic
intracerebral hemorrhage in the tPA group.

Thus, at three months, there was a significant benefit to tPA in
the NINDS group and only a trend in the LMWH study. Interestingly, the
numbers are very similar at three months in these two studies; the reason
the LMHW group did not reach statistical significance is probably because
of the smaller number of patients in that trial. At six months, there was
a significant benefit in the LMWH study; we do not have corresponding data
for the NINDS study.

Why is so much more being made of the NINDS study than of the LMWH
study? I suspect there are a number of reasons. The LMWH study is a smaller
trial, performed in China. There is a bias in the United States towards
trials that are larger and that are performed here. Furthermore, the early
use of a thrombolytic agent seems intuitively a more direct attack on cerebral
thrombosis than using heparin given within 48 hours of a CVA. The dramatic
appeal of a "clot-buster" is not to be underestimated.

Nevertheless, you raise a very valid point. The benefit shown by
LMWH was impressive, did not require administration within 3 hours, and
did not come at the expense of an increase in intracerebral hemorrhage.
This certainly warrants further investigation. I wonder if any neurologists
are using this approach in practice? --mwj

Date: June 2, 1999
From: The Bear [ysehgal@cancom.net]

Whenever I see a "drug-company" trial of an expensive drug, I get suspicious.
Doesn't it bother anyone that the outcome measure was changed at three
months (they completely made-up a "global score" because the actual outcome
measures wouldn't have been positive). This is totally a matter of
data manipulation to prove a predetermined goal and has nothing to do with
science. The lack of effect has been confirmed by several studies
into TPA and Streptokinase, and yet people still jump on the tPA bandwagon,
and the danger of intracerebral hemorrhage has been confirmed again and
again. This is another reason for journals to have a requirement
to disclose drug-company funding.

Yogi Sehgal,
Terrace Bay ON, Canada
reply to: yogman1@hotmail.com

In the article, it is not specified whether the "global
statistic" was developed before data analysis or not. However, most of
the individual measurements which were components of the global statistic
also reached statistical significance. Thus, it is not likely that
the outcome measure was changed at three months, since the actual component
outcome measures were, in fact, positive. --mj

June 30, 2000
From: Charles A. Pilcher, MD

As best as I can calculate it, the NNT for tPA in stroke is about 25% as
great as the NNH in the NINDS study. In other words, we'll make 1 patient worse
for every 4 we make marginally better. And "worse" means death for
half of those made "worse."

The June 21, 2000, issue of JAMA editorializes on stroke centers, where the
NNT is estimated to be about 18. I suspect the NNT for Coronary Care Units is a
bit better than 18, like maybe 1?

I remain open but skeptical. We're undoubtedly on the right track, and this
is only the first battle in the war. To read from most authors, one would think
the war was already won.

I sympathize with your feelings, although the analogy with CCU's doesn't
quite hold up. If the NNT for CCU's were truly 1, this would imply that
every single patient admitted to a CCU would have done worse if not admitted
to such a unit, clearly not the case. Of course, you are right that the
"war" is nowhere near won with IV thrombolytics as treatment for
stroke. --mj